Primary Epstein-Barr virus (EBV) infection may be asymptomatic, or it may be manifest clinically as heterophile-positive infectious mononucleosis. During primary infection the virus gives rise to a population of EBV-transformed B-lymphocytes which are capable of continuous in vitro cultivation. An integrated humoral and cell mediated immune response which includes polyclonal immunoglobulin production and the appearance of an atypical lymphocytosis terminates the proliferation of this subpopulation of EBV-transformed B-lymphocytes. The host range of the virus which is restricted to B-lymphocytes of man and of higher primates has precluded the development of suitable animal models for investigation of the immunologic response to EBV in vivo. This project will examine the immunologic response to EBV by in vitro techniques which allow investigation of several immunologic functions analagous to those operative in vivo during primary EBV infection. The mechanism by which proliferation of EBV-transformed B-lymphocytes is terminated will be invesigated in a quantitative in vitro outgrowth suppression system. The possible contributing role of interferon to the cell-mediated immune response to EBV, and the effects of corticosteroids and of antivira agents of this immune response will be studied. Immunologic factors which account for increased excretion rates of EBV by immunosuppressed patients, and the mechanism by which primate type-C oncoviruses enhance expression of latent EBV will also be investigated. The mechanism of EBV-induced polyclonal B-cell activation, and the pathophysiologic significance of aberrant immunoglobulin production during infectious mononucleosis will be studied in a hemolytic plaque forming cell system. It is anticipated that these investigations may lead to the development of chemotherapeutic and immunologic treatment modalities which will have clinical utility fo EBV infections. In addition, these studies will provide insights into the biology of latent viral infections, and into the normal immunoregulation of immunoglobulin production.